Compositions and methods for enhancing or treating female sexual response

ABSTRACT

The present invention relates to compositions and methods for enhancement of sexual pleasure and disorders related to sexual pleasure especially in mammalian females. The present invention relates to all aspects of modulating the female sexual response, including female sexual dysfunction such as female sexual arousal disorders (FSAD), orgasmic disorders, sexual pain disorders and enhancing female sexual pleasure and satisfaction. The present invention relates to compositions comprising botanical extracts and active agents which are useful to treat or affect any of the aforementioned conditions. The present invention relates to a composition, preferably for topical or local use, which comprises one or more of the following ingredients; including, but not limited to, borage seed oil,  Angelica pubescens  root and other Angelica species,  Coleus forskohlii  extract, vinpocetine, ferulic acid, magnesium, ascorbyl palmitate, capric triglyceride, caprylic triglyceride, silica and equivalents thereof.

This application claims the benefit of U.S. Provisional Application No.60/214,472, filed Jun. 27, 2000, which is hereby incorporated byreference in its entirety.

DESCRIPTION OF THE INVENTION

While increased understanding of the pathophysiology of male erectiledysfunction progressed rapidly in the past decade and led to newtherapeutic modalities, little has been done to address similar issuesin women. Accordingly, the present invention relates to all aspects ofmodulating the female sexual response, including female sexualdysfunction, such as female sexual arousal disorders (FSAD), orgasmicdisorders, and sexual pain disorders, and enhancing the female sexualexperience. In particular, the present invention relates tocompositions, articles of manufacture, methods of preparation thereof,methods of use thereof, etc., for conditions, disorders, and diseasesrelated to female reproductive physiology systems, especially thoseinvolved in the female sexual response.

Compositions comprising botanical extracts, active agents, etc., can beproduced and used in accordance with the present invention that areuseful to treat or affect the female sexual response. For example, thepresent invention relates to compositions, preferably for topical orlocal use, which comprise one or more of the following ingredients,including, but not limited to, borage seed oil and other sources ofgamma linolenic acid (GLA), Angelica pubescens root, Coleus forskohliiextract, vinpocetine, and other naturally-occuring cyclic adenosinemonophosphate (cAMP) and cyclic guanine monophosphate (cGMP)phosphodiesterase (PDE) inhibitors and equivalents thereof. Thecompositions can produce one or more of the following pharmacologicaleffects, including, but not limited to, increases in localized nitricoxide, cAMP production and/or elevation, cGMP production and/orelevation, prostaglandin E₁ production, inhibition of prostaglandin E₁breakdown, calcium channel antagonism, phosphodiesterase inhibition,anti-oxidation, vasodilation, smooth muscle relaxation, etc.

A useful composition in accordance with the present invention cancomprise borage seed oil or other borage plant parts, preferably fromBorago officianalis. The borage plant (e.g., leaves, roots, and seeds)comprises a complex mixture of defined and undefined constituents,including, e.g., acetic acid; alkaloids; allantoin; amabiline;arabinose; ascorbic-acid; beta-carotene; bomesitol; calcium; choline;cobalt; dhurrin; fat; fiber; galactose; gamma linolenic acid; glucoseplant; intermedine; lycopsamine; magnesium; malic acid; mucilage;niacin; phosphorus potassium; protein; pyrrolizidines; resin;riboflavin; rosmarinic acid; silicic acid; sodium; supinine; supinineviridiflorate; thiamin and zinc. A preferred bioactive ingredient ofBorage is gamma linolenic acid (GLA) having a molecular weight of 278.GLA is a polyunsaturated fatty acid (PUFA) belonging to the group offatty acids called omega-6 or N-6 fatty acids because of the presence ofa double bond between the 6th and 7th carbon. GLA is found predominantlyin the seed of the Borage plant, but is also found in evening primroseseed oil and other botanical and natural sources.

Borage seed oil can be prepared by any suitable method, preferablymethods which extract GLA and other bioactive agents, such as coldpressure extraction, screw pressure extraction, solvent extraction,supercritical fluid extraction, etc. A borage seed oil can comprise anyamount of GLA, preferably, e.g., by weight, at least about 10%, 15%,20%, 25%, 30%, etc. The oil preferably is free of compounds which aretoxic, or deleterious to mammals, such as alkaloids, pyrrolizidine, etc.

Borage seed oil can be present in a composition of the present inventionin any effective amount, e.g., 1-100%, 10-95%, 20-95%, 30-95%, 50-95%,70-90%, 60-90%, 80%, 81%, 82%, 83%, 84%, 84.25%, 85%, 86%, 87%, etc.,w/w (i.e., weight of ingredient/weight of total composition).

In addition to borage seed oil, other sources of GLA can be utilized,including, e.g., purified or isolated GLA, botanical extracts, such asevening primrose oil (e.g., Oenothera biennis and Oenotheralamarckiana), black currant oil, spirulina, oils from the seeds of theRibes family, etc.

Borage seed oil has a variety of beneficial effects and activities,including, but not limited to, e.g., inhibiting platelet aggregation,lowering blood pressure, anti-inflammatory activity, vasodilation,prostaglandin promoting activity, PGE₁ promoting activity (see, below),promoting circulating hormones, causing smooth muscle relaxation, etc.Borage seed oil can be included in a composition of the presentinvention in amounts which are effective to achieve one or more of theaforementioned effects.

A composition of the present invention can also comprise Angelica, suchas Angelica archangelica, Angelica sinensis, Angelica sylvestris,Angelica officinalis, archangel, European angelica, garden Angelica,Angelica acutiloba, preferably Angelica pubescens which is also known asDu Huo or Du Huo Radix. Angelica root is preferred, but other parts ofthe plants can be used as well. Angelica contains a wide and complexvariety of different constituents, of a defined and undefined nature.Preferred bioactive compounds are flavinoids, flavones and coumarins,preferably, osthole or 7-methoxy-8-(3-methylpent-2-enyl)coumarin, andalpha-angelicalactone. Other coumarins, include, e.g., meranzin hydrate,nodakentin, marmesinin, columbianadin, columbianetin, bergapten,heramandiol, 6-alkylcoumarins, angelol-type coumarins, byak-angelicin,ferulin, oxypeucedanin, umbelliprenin, imperatorin, neobyakangelicin,prenylcourmarins, glabralactone, anpubesol, angelical, angelin,furanocourmins, and derivatives thereof. Other bioactive agents include,e.g., linoleic acid, osthenol, falcarindiol, numerous flavinoids andflavones, 11(S), 16(R)-dihydroxyoctadeca-9Z,17-diene-12,14-diyn-1-yl-acetate, xanthotoxin, umbelliferone, ferulicacid, magnesium, and derivatives thereof.

Angelica possesses a number of pharmacological activities, including,but not limited to smooth muscle relaxant activity, phosphodiesteraseinhibition, calcium antagonist activity, cycloxygenase and5-lipoxygenase inhibition (e.g, Liu et al., Pharm. Bio., 36(3):207-216,1998), etc. Coumarins, and osthole in particular, have been identifiedto display activities such as, inhibition of platelet aggregation,inhibition of smooth muscle contraction, smooth muscle relaxation (e.g.,Che-Ming et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 349:202-208,1994), inhibition of calcium flux, cyclic nucleotide (such as cGMP andcAMP) phosphodiesterase inhibition, increase in cAMP and cGMP levels,anti-proliferative, anti-inflammatory (Yuh-Fung et al., Planta Medica,61(1):2-8, 1995), enhancement of the increase of cAMP and cGMP inducedby forskolin, vasorelaxation, neurotransmitter receptor binding, such asGABA, 5HT-1A, D-2, and D-1 receptors (Jyh-Fei et al., Proceedings of theNational Science Council Republic of China, Part B, Life Sci.,19(3):151-158, 1995), etc. Alpha-angelicalactone also possesses variousactivities, including, e.g., calcium antagonism. See, e.g., Entman etal., J. Clin. Invest., 48:229-234, 1969. Ferulic acid, another componentof Angelica root also has been shown to scavenge oxygen free radicalsand increase intracellular cAMP and cGMP. See, e.g. Zheng R L, Zhang H.,Free Radic Biol Med., 22(4):581-586, 1997. Preferred activities ofAngelica are cyclic nucleotide phosphodiesterase inhibition, calciumantagonism, oxygen free radical scavenging, smooth muscle modulation, aseither vasorelaxant or vasodilatory.

A composition of the present invention can comprise any effective amountof Angelica, preferably Angelic pubescens root, e.g., 0.1-99%, 0.1-80%,0.1-50%, 0.5-8%, 1%, 2%, 3%, 4%, 5%, etc. w/w.

In another embodiment of the present invention, a composition canfurther comprise Coleus forskohlii, preferably from its tuber or roots.The plant is a member of the Labiatae family and grows as a perennial.It is native to India, Nepal, Sri Lanka, and Thailand. See, e.g., TheWealth of India, Vol. II, C.S.I.R., India, 1950, Page 308. Coleusforskohlii comprises a diverse and complex mixture of compounds, e.g.,diterpenes, and derivatives thereof. A preferred bioactive diterpenecompound is forskolin and related diterpenes.

Coleus forskohlii can be utilized in any form which is effective,including, but not limited to dry powders, grounds, emulsions, creams,extracts, and other conventional formulations. Extracts can be preparedroutinely, e.g. by contacting the plant parts with a suitable solvent toextract a diterpene or other compound from the material (e.g., see, U.S.Pat. No. 4,118,508, JP 11292777, and JP 6133731 for extractionprocesses). Any amount of Coleus which is effective can be utilized incompositions of the present invention, e.g., at least about 0.1-99%,0.1-80%, 0.1-50%, 0.5-8%, 1%, 2%, 3%, 4%, 5%, etc. w/w of an 80%extract.

Coleus forskohlii, particularly forskolin and related diterpenes, have anumber of biological activities, including, smooth muscle relaxation,adenylate cyclase stimulation, elevation of levels of cAMP,anti-inflammatory, ant-spasmodic, etc. Since forskolin and relatedditerpenes stimulate adenylate cyclase, resulting in the production ofthe second messenger cAMP, any biological process mediated by cAMP cantherefore be stimulated by administration of Coleus forskohlii.

Compositions of the present invention can also comprise vinpocetine(eburnamenine-14-carboxylic acid ethylester) and derivatives thereof.Vinpocetine is a naturally-occurring product found, e.g., in vinca minor(periwinkle). It can be extracted from natural sources, such as vinca,or produced synthetically. Various derivatives of vinpocetine can beutilized, including salts. For methods of synthesis of vinpocetine andderivatives, e.g., U.S. Pat. No. 4,035,370; Szabo et al., Arch. Pharm.,316:629-638; Tungler et al., J. Mol. Catalysis, 108:45-152, 1996; U.S.Pat. No. 4,749,707 (e.g., citrate and phosphate salts). Vinpocetine andits derivatives have various activities and effects, including, e.g.,phosphodiesterase inhibition, selective PDE type I inhibition,vasodilation activity, smooth muscle relaxation, increases in levels ofcAMP and/or cGMP. etc.

Any amount of vinpocetine which is effective can be utilized incompositions of the present invention, e.g., at least about 0.1-99%,0.1-80%, 0.1-50%, 0.5-8% 1%, 2%, 3%, 4%, 5%, etc.

In addition to the above-mentioned botanical extracts, or as analternative thereof, a composition of the present invention can compriseany agent which possesses one of more of the biological activitiesassociated with said botanical extracts.

For example, the present invention also relates to agents having “PGE₁promoting activity.” As mentioned, one of the major constituents ofborage seed oil is GLA. GLA is a precursor of prostaglandin E1 (PGE₁), apotent biological effector molecule. PGE₁ has many physiologicaleffects. While not wishing to be bound to any theory, it is believedthat at least some of the beneficial effects produced by borage seed oilis mediated by its delivery of a precursor to the PGE₁ metabolicpathway, thereby stimulating production of PGE₁. Thus, any compound,mixtures thereof, compositions, botanicals, etc. which comprise a PGE₁or a PGE₁ precursor can be characterized as having “PGE₁ promotingactivity,” e.g., causing the production of PGE₁, or possessing PGE₁activity.

Another useful class of agents in accordance with the present inventionare those which elevate levels of cyclic nucleotides, such as cAMP andcGMP, e.g., by inhibiting phosphodiesterases which hydrolyze the cyclicnucleotides, by stimulating adenylate cyclase, or receptors coupledthereto, by acting on G-proteins, etc. In accordance with the presentinvention, any amount of elevation or increase of cyclic nucleotidewhich is effective to elicit a desired result, such as treating FSD,enhancing sexual arousal, etc. Amounts of increase as compared to normalcan be at least 5%, 10%, 50%, 75%, 90%, 1-fold, 2-fold, 5-fold, 10-fold,20-fold, etc. These increases can be sudden, transient over a fewminutes, localized, etc., as long as the desired effect is achieved,e.g., modulating the female sexual response.

Elevation of levels of cyclic nucleotides can be accomplished by cyclicnucleotide phosphodiesterase (PDE) inhibition. There are a number ofdifferent cyclic nucleotide phosphodiesterase isoenzymes, includingtypes I, II, III, IV, V, VI, and VII. See, e.g., Nicolson et al., 1991.PDE inhibitors can be non-selective (e.g., theophylline or caffeine), orselective for one or more PDE isoenzymes. Selective inhibitors, include,I (vinpocetine), III (milrinone, amrinone, pimobendan, cilostamide,enoximone, peroximone, vesnarinone), IV (rolipram, R02—1724), and V(zaprinast, dipyridamole). Other useful PDE inhibitors include compoundsdisclosed in U.S. Pat. No. 5,958,926.

In addition to elevating levels of cAMP through inhibition of PDEs(e.g., utilizing Angelica pubsescens root extract and other species ofAngelica) cAMP levels can be elevated by directly stimulating adenyatecyclase and causing synthesis of cAMP, e.g., using Coleus forskohlii,and derivatives thereof. Useful forskolin derivatives, and theirsynthesis, are disclosed in, e.g., EP 222,413, U.S. Pat. Nos. 5,789,439,5,350,864, 5,206,241, 5,177,207, 5,145,855, 5,093,336, 4,999,351, and4,134,986.

Compositions can be administered in any form by any effective route,including, e.g., oral, parenteral, enteral, intraperitoneal, topical,local, dermal, transdermal, ophthalmic, nasally, nasopharyngealabsorption, local, topical, non-oral, aerosal, inhalation, subcutaneous,intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial,rapid infusion, intravenously, long-release implants, etc.

In preferred embodiments of the invention, compositions are administeredto the external female genitalia and/or vaginally, e.g., as a vaginalcream, foam, gel, jelly, liquid, emulsion, solution, suspension, cream,spray, powder, suppository, tablet, device, etc. For example, acomposition can be preferably applied to the female external genitalia,such as the mons pubis, labia majora and minora, hymen, clitoris,prepuce of the clitoris, vestibule of the vagina, and/or vestibularglands. The external genitalia is also called the vulva or pudendum.Compositions can also be applied to the internal wall of the vagina,e.g., to the adventia, muscularis, mucosa, and rugae.

A composition of the present invention can also be administered by or inthe form of a device, such as a cartridge, diaphragm, female mechanicalbarrier-type device, feminine cap (e.g., U.S. Pat. Nos. 4,858,624,4,989,618, and 5,207,232), film, intrauterine barrier-type device,sponge, tampon, osmotic drug delivery device (e.g., U.S. Pat. Nos.5,795,591, 4,475,916, and 4,093,708), ring, or sheath. Such devices cancarry the composition in any effective manner, e.g., a device can beimpregnated or coated with the composition, or fitted with a carrierelement, such as a film (e.g., U.S. Pat. No. 5,529,782), or polymericmaterial, etc., that contains composition. The device can then beinserted into the vagina where delivery is effected. See, e.g., U.S.Pat. No. 4,317,447. A device can be a sponge-like structure, such as apolymeric sponge tampon, which contains a composition of the presentinvention. See, e.g., U.S. Pat. No. 4,393,871. Such a device can beinserted into the vagina prior to intercourse. The device can also bereusable. In the case of devices, it can be advantageous to formulatethe composition with compounds, such as water-soluble polymers ordissolvable materials, which disintegrate in the vaginal fluids, therebyreleasing the active agents. Any suitable polymer can be used, e.g., asdescribed in U.S. Pat. No. 5,840,685 5,393,528, 5,084,277, 4,835,138,4,323,548, and 4,322,399.

A composition of the present invention can also be administered by amale condom, e.g., by applying the composition to the condom prior toinsertion into the vagina, e.g., in combination with other lubricants,or, as a dry or wet film or coating on the exterior of the condomsurface. See, e.g., U.S. Pat. No. 5,954,054.

In general, any delivery means, including devices, polymers, etc., thatare used to deliver agents vaginally can be utilized in accordance withthe present invention, such as means for delivering antiviral agents,bacteriocides, contraceptives, hormones, spermicides, virucides,lubricants, etc.

Compositions of the present invention can further comprise other activeagents, including, e.g., contraceptive agents, spermicidal agents, suchas, e.g., nonoxynol-9, octoxynol, menfegol, benzalkonium chloride,peroxygen compounds or hydrogen peroxide (e.g., U.S. Pat. No.5,778,886), bacteriocides, germicides, antiviral agents, virucides,vasodilators, agents which increase vaginal lubrication (e.g., hydriodicacid syrup as disclosed in U.S. Pat. No. 5,470,588), etc.

In addition, compositions of the present invention can further compriseany agent which enhances the sexual response and/or treat diseases andconditions related to sexual dysfunction. Such agents include, e.g.,apomorphine (e.g., U.S. Pat. No. 5,945,117), nitric oxide releasingcompounds (e.g., U.S. Pat. No. 5,877,216), Ginkgo (e.g., U.S. Pat. No.5,897,864), hydriodic acid (U.S. Pat. No. 5,470,588), agents disclosedin U.S. Pat. No. 4,521,421.

The compositions of the present invention can further comprise anypharmaceutically acceptable carrier. By the phrase, “pharmaceuticallyacceptable carrier,” it is meant any excipient, solvent, vehicle, inertingredient, etc., which is formulated with the active ingredients of apharmaceutical composition, such as the standard agents described, e.g.,in Remington's Pharmaceutical Sciences, Eighteenth Edition, MackPublishing Company, 1990. Examples of suitable carriers are well knownin the art and can include, but are not limited to, water, phosphatebuffered saline solutions, phosphate buffered saline containing POLYSORB80, emulsions such as oil/water emulsion and various type of wettingagents, salt solutions, alcohols, gum arabic, vegetable oils, benzylalcohols, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles(e.g., corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate), etc. Carriers also include,e.g., milk, sugar, certain types of clay, silica, gelatin, stearic acidor salts thereof, magnesium, magnesium stearate and other forms or saltsof magnesium, or calcium stearate, talc, vegetable fats or oils, gums,glycols, propylene glycol, buffers, antimicrobial agents, preservatives,flavor, fragrance and color additives, gelatin, carbohydrates such aslactose, amylose or starch, talc, silicic acid, viscous paraffin,perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritolfatty acid esters, hydroxy methylcellulose and the like. Other additivesinclude, e.g., antioxidants and preservatives, coloring, flavoring anddiluting agents, emulsifying and suspending agents, such as acacia,agar, alginic acid, sodium alginate, bentonite, carbomer, carrageenan,carboxymethylcellulose, cellulose, cholesterol, fatty acids,triglycerides and esters of fatty acids, fatty alcohols, gelatin,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, octoxynol 9, oleyl alcohol, povidone,propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters,stearyl alcohol, tragacanth, xanthan gum, and derivatives thereof,solvents, transdermal enhancers (ethanol, propylene glycol, water,sodium oleate, leucinic acid, oleic acid, capric acid, sodium caprate,capric/caprylic triglyceride, silica, lauric acid, sodium laurate,neodecanoic acid, dodecyl-amine, cetryl lactate, myristyl lactate,lauryl lactate, methyl laurate, phenyl ethanol, hexa-methylenelauramide, urea and derivatives, dodecyl N,N-dimethylamino acetate,hydroxyethyl lactamide, phyophatidylcholine, sefsol-318 (a medium chainglyceride), isopropyl myristate, isopropyl palmitate, palmitic acid,several surfactants, including poly-oxyethylene (10) lauryl ether (Brij361 R), diethyleneglycol lauryl ether (PEG-2-L), laurocapram (Azone;1,1-dodecylazacycloheptan-2-one), acetonitrile, 1-decanol,2-pyrrolidone, N-methylpyrrolidone, N-ethyl-1-pyrrolidone,1-Methyl-2-pyrrolidone, 1-lauryl-2-pyrrolidone, sucrose monooleate,dimethylsulfoxide (DMSO) about 80% concentration required,decylmethylsulfoxide (n) enhances primarily polar or ionic molecules(soluble in ethanol), acetone, polyethylene glycol 100-400 MW,dimethylacetamide, dimethylformamide, dimethylisosorbide, sodiumbicarbonate, various N₇₋₁₆-alkanes, mentane, menthone, menthol,terpinene, D-terpinene, dipen-tene, N-nonalool and limonene, skinpenetration enhancers (e.g., lecithin), and miscellaneous ingredientssuch as microcrystalline cellulose, citric acid, dextrin, dextrose,liquid glucose, lactic acid, lactose, magnesium chloride, potassiummetaphosphate, starch, and the like.

As mentioned, compositions of the present invention can comprise one ormore of the following ingredients, e.g., borage seed oil, Angelicapubescens root, Coleus forskohlii extract, magnesium and its salts,ferulic acid, vinpocetine, and equivalents thereof, in any binary,trinary, etc., combination. Such ingredients can be present insynergistic amounts. Examples of topical compositions, include, e.g.,binary combinations, such as an effective amounts of borage seed oil,and Angelica pubescens root; effective amounts of borage seed oil, andColeus forskohlii extract; effective amounts of Angelica pubescens root,and Coleus forskohlii extract; and quarternary combinations, such aseffective amounts of borage seed oil, Angelica pubescens root, Coleusforskohlii extract, and vinpocetine. Such compositions can furthercomprise pharmaceutically-acceptable excipients, skin- and mucosalpenetration enhancers, etc. In preferred embodiments, included asexcipients are, e.g., de-ionized water (e.g, about 0.5-50%, preferably5%, concentration), Span 80 (sorbitan monooleate (e.g., 0.2-20%,preferably 2%, concentration), lecithin (e.g., egg or soyphosphatidylcholine (e.g., e.g., 0.2-20%, preferably 2%, concentration),lavenden for body oils by Flavor and Fragrance Specialties (0.05-1,25%,preferably 0.25%), Blackberry Musk for body oils by Flavor and FragranceSpecialties (0.1-2.5%, preferably 0.5%) or other flavors and fragrances,glycerin (e.g., 2-10% w/w), saccharin or other sweetening agents, andmonsodium Gaunosine Mono Phosphate (flavor enhancer), silica, ferulicacid and other forms of ferulate, magnesium sulfate and other forms ofmagnesium, vitamin E acetate and other forms of tocopherol, and ascorbylpalmitate and other forms of ascorbic acid along with otheranti-oxidants and stability enhancers. Ingredients, and amounts ofingredients, can be adjusted such that the compositions possess minimalirritation to the female reproductive organs. Ingredients can also beincluded that enhance the cosmetic appeal (e.g., enhancing the smell,feel, etc.) of the compositions, but which are inert as far as enhancingthe sexual response, e.g., enhancing the smell, feel, etc., of acomposition.

A quarternary topical composition can comprise, e.g., a) borage seed oiland/or evening primrose oil is 10-99% w/w of said composition; b)Angelica pubescens is 0.001-99% w/w of said composition, c) Coleusforskohlii is 0.001-8% w/w of said composition, and d) vinpocetine is0.001-8% w/w of said composition. This composition can further comprise,e.g., e) magnesium 0.001-90%, f) ferulic acid 0.001-10%.

The present invention also relates to methods of using any of thementioned compositions, e.g., for treating or affecting diseases andconditions associated with sexual function, especially associated withthe female reproductive system, such as for treating sexual dysfunction,facilitating sexual arousal, enhancing or improving sexual response, orenhancing or improving sexual pleasure, comprising administering aneffective amount of a composition in accordance with the presentinvention. By “sexual functioning,” it is meant any activity associatedwith the genitalia, such as sexual intercourse. The methods are usefulto treat various types of female sexual dysfunction (FSD), such asfemale sexual arousal disorder (FSAD), desire disorders, orgasmicdisorders, and sexual pain disorders. Premenopausal and post-menopausalwomen can be treated.

The stages of female sexual activity include excitement (arousal),plateau, and orgasm. The arousal response is a physiological andpsychological process involving, e.g., muscle relaxation,vasocongestion, vasodilation, and muscular contraction. The clitoriswhich contains a rich supply of sensory endings becomes erect as aresult of vasocongestion. During intercourse, the vaginal epitheliumbecomes highly congested and secretes a mucus-like lubricant which is anexudate. See, e.g., Human Physiology, Vander et al., Fifth Edition,McGraw-hill Publishing Company, 1990, e.g., Page 628; Current MedicalDiagnosis, Tierney et al., Eds., 1997, e.g., Pages 962-965; U.S. Pat.No. 5,958,926, especially Column 7-9. Compositions of the presentinvention can particularly facilitate and/or enhance arousal and orgasm,e.g., by enhancing associated vasocongestion and vasodilation andsensory input.

Sexual arousal disorders, e.g., inability to become aroused or inabilityto attain or maintain sufficient sexual excitement, female impotence,vaginismus, frigidity, disorders of sexual desire, e.g., absence oflibido, decreased or loss of sensation, etc. can be treated or affectedin accordance with the present invention. In addition, sexual paindisorders, such as painful intercourse, or dyspareunia, can be treated.The latter can be caused by a number of factors, including, e.g.,endometriosis, vaginismus, insufficient lubrication of the vagina, etc.FSAD can be manifested by a patient as a lack of subjective excitement,a lack of genital lubrication or swelling, or another somatic responses.Disorders of arousal include, but are not limited to, lack or diminishedvaginal lubrication, decreased clitoral and labial sensation, decreasedclitoral and labial engorgement, lack of vaginal smooth musclerelaxation, and disorders involving hormonal status. Compositions of thepresent invention can treat any of the mentioned conditions associatedwith female sexual dysfunction.

In addition, the compositions are useful for enhancing or improvingsexual response and/or enhancing or improving sexual pleasure andsensation. By the terms, “enhance” or “improve,” it is generally meantthat administration of a composition increases the subject'ssatisfaction with the sexual activity as compared to the activity whenin the absence of the composition. This includes, e.g., enhancement ofvaginal wetness, warmth, engorgement, sensitivity, sensation, tingling,arousal, orgasm, quicker to arousal, quicker to orgasm, and enhancementof any of the above-mentioned conditions (e.g., clitoral and labialsensation or vaginal smooth muscle relaxation), etc. Any amount ofincrease in satisfaction can be achieved, including, e.g., 1%, 5%, 10%,50%, 100%, 2-fold, etc. Satisfaction can be determined by any suitablemethod, e.g., a survey or questionnaire in which a user is asked toassess, after using a composition of the present invention, changes inthe genital area and sexual pleasure.

By the term “administering,” it is meant that a composition is deliveredto the subject in such a way that it can achieve the desired purpose,e.g., treating a condition or disease associated with sexual function.As mentioned, such composition can be administered by any effectiveroute, preferably vaginally, such as topically or locally. Compositionsof the present invention can be administered to any suitable subject,preferably human females, but also to females of other species, such asapes, monkeys, chimpanzees, pets, such as dogs, cats, rats, hamsters,and mice, horses, pigs, cows, sheep, and other domestic animals, andmales of any species.

In addition to females having any of the aforementioned conditions,suitable female subjects, include, e.g., females having illnesses thatinterfere with sexual arousal, such as diabetes mellitus,hypothyroidism, pelvic disorders, neurological disorders (e.g., multiplesclerosis), muscular disorders (e.g., muscular dystrophy), andpsychological disorders (guilt, anxiety, depression, fatigue, orinterpersonal conflicts), conditions that lead to failure of thevasocongestion response, vaginal dryness, anorgasmic females,intermittently orgasmic females, orgasmic females desiring greatersexual response, sexual-related failures associated with age, neurosis,females having sexual desire disorders, orgasmic dysfunction,drug-induced sexual dysfunction (e.g., associated with oralcontraceptives, anti-hypertensives, tranquilizers, SSRIantidepressants), hypoactive sexual desire (HSD), postmenopausal women,etc.

Administration of compositions of the present invention can alleviate,improve, or ameliorate any of the mentioned conditions. In addition,sexual response can be improved, e.g., decreasing foreplay (e.g., thetime usually required for a subject to reach arousal), decreasinglatency time between orgasms, decreasing the time to reach orgasm, andfacilitating orgasm and multiple orgasm.

An effective amount of a composition is administered to a targetsubject. Effective amounts are such amounts that are useful to achievethe desired effect, preferably a beneficial, pleasurable or therapeuticeffect as described above. Such amounts can be determined routinely,e.g., by administering different dosages to subjects and surveying orquestioning such subjects after sexual activity about their preferencesand the effectiveness of the treatment. Amounts can be selected based onvarious factors, including the age, health, gender, and weight of thesubject.

EXAMPLES Example 1

Preparation of Base Oil

Freshly milled Angelica pubescens root was mixed in a 1:1 weight/weightratio (other ratios, as described above can be used, e.g., 0.8:1) withborage seed oil (e.g., containing 20-26% GLA content, depending on thespecific source). Lavender for Body Oils and Blackberry Musk for BodyOils (obtained from Flavor and Fragrance Specialties) were each added ata concentration of 10 mg/ml. (Optionally, in some cases, primrose oil(e.g., 9% GLA content) was added to the base oil for a finalconcentration of 1% primrose oil.) This mixture was stirred rapidly in awater-jacketed blender, and heated at 80° C. for a 3-hour period. Theresulting finely-divided solid/oil mixture was cooled to roomtemperature, filtered once through a 20-micron filter, and thenrefiltered through a 5-micron filter. The base oil mixture was brightgold-colored with a mild odor of Angelica pubescens.

Example 2

Preparation of a Gel Composition for Topical Application

A composition was formulated comprising 70% of the base oil producedaccording to Example 1. To this oil, Coleus forskohli (containing about80% forskolin) was added to the base oil for a final concentration of 10mg/ml base oil. Vinpocetine was to this at a final concentration of 10mg/ml base oil.

The following further ingredients were added to the mixture, but areoptional ingredients: magnesium sulfate (USP or FCC) at a concentrationof 40 mg/ml, capric/caprylic triglyceride (at about 25% w/w) to enhancepermeation, ferulic acid from Angelica species at 1-20 mg/ml, acorbylpalmitate to stabilize oil and retard oxidation, alpha-tocopherol andtocopherol acetate to stabilize oil and retard oxidation, soy lecithingranular USP or FCC) at a concentration of 1-50 mg/ml of base oil, span80 (sorbitan monooleate) at 1-10 mg/ml of base oil, fumed silica (atabout 4% w/w) to form a gel version of the oil, and saccharin. Propyleneglycol can be added to increase lubricity, but were not used in the caseexamples below.

The above mixture was heated and rapidly stirred in a water bath set at70° C. for 30 minutes. After cooling to room temperature, the mixturewas filtered through once through a 20-micron filter, and thenrefiltered through a 5-micron filter. The resulting mixture iscentrifuged at 11,000 rpm for 5 minutes, and the oil portion iscollected. To further clarify the product, the mixture is filtered,under vacuum, through a 5-micron filter, and then placed in an amberglass screw top container and stored at room temperature.

Example 3

Preparation of an Oil Composition for Topical Application

To prepare an oil for topical application, a composition is formulatedin accordance with Example 2, but fumed silica is omitted, andoptionally capric/caprylic acid, as well.

Case Examples Case Example 1

A multi-parous perimenopausal forty-two year old woman in a monogamousrelationship with self-described complaints of difficulty with sexualarousal and difficulty with vaginal lubrication during sex volunteeredto use a composition produced according to Example 2. With the consentof her partner, she applied approximately 0.6 ml to her clitoris andlabial areas during foreplay. The woman indicated a pleasurable gradualwarming sensation to the areas of application. She reported that withinfive minutes of application, the warming had reached a plateau and thather clitoral sensation was increased. Also her labia began to feel plumpor swollen (aroused). She reported no difficulties with lubricating andclaimed that sex was much more pleasurable and that her vaginalsensation had increased. Neither her nor her partner reported anyadverse effects. Her partner reported that she was clearly more sexuallyaroused than usual and that her vagina was warmer than usual. Bothpartners indicated they would try more samples if provided.

Case Example 2

A multi-parous post-menopausal fifty-three year old woman in amonogamous relationship with self-described complaints of decreasedclitoral and vaginal sensation volunteered to use a composition producedaccording to Example 2. With her partner's consent, she appliedapproximately 0.66 ml to her clitoral and labial areas and applied theremainder of the vial (0.44 ml) to her partner's penis during foreplay.The couple reported approximately ten minutes of foreplay. The womanclaimed feeling a gradual warming and heightened sensation of herclitoris and vagina within about five minutes after application. Herpartner also noticed a slight warming effect of his penis. The couplereported engaging in intercourse after about ten minutes of foreplay.The woman claimed that the composition significantly improved hersensations during intercourse and overall had increased her sexualsatisfaction. Her partner claimed that from the looks (expressions) onher face, she seemed to enjoy his thrusting more than usual. Neitherpartner reported any adverse effects. Both partners indicated they wouldregularly use the composition if provided with more samples.

Case Example 3

A monoparous thirty-four year old woman in a monogamous relationship whodescribed herself as sexually normal volunteered to use a compositionproduced according to Example 2. With the consent of her partner, sheapplied approximately 0.7 ml to her clitoral and labial areas duringforeplay. After about five minutes she reported a pleasurable andgradually building warming sensation that reached a plateau of intensityin about ten minutes. She claimed that the composition made it easier toreach orgasm and made it more intense than usual. She also claimed itspleasurable effects lasted for about forty-five minutes. She reportedthe composition significantly heightened her sexual experience and woulduse it regularly if she could get more samples. Neither partner reportedany adverse reactions.

Case Example 4

A thirty-eight year old woman volunteered to use 0.5 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about five minutes. c) That thechange in sensation lasted approximately one hour. d) That sheexperienced enhanced warmth, tingling and arousal. e) That after usingthe product, intercourse was more pleasurable and satisfying thannormal. f) That her vaginal lubrication seemed to be the same as always.g) That her ability to achieve orgasm was unchanged. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it on special occasions andwhen she needed a boost. j) That she did not experience any unpleasantor unwanted effects.

Case Example 5

A thirty year old woman volunteered to use 0.5 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about two to three minutes. c) Thatthe change in sensation lasted approximately forty minutes. d) That sheexperienced enhanced wetness, warmth, enhanced fullness (engorgement)and enhanced sensitivity. e) That after using the product, intercoursewas more pleasurable and satisfying than normal. f) That her vaginallubrication seemed to be more than usual. g) That her ability to achieveorgasm was unchanged. h) That the product enhanced her sexual experienceand would like to continue using it. i) That she would purchase theproduct and use it routinely. j) That she did not experience anyunpleasant or unwanted effects.

Case Example 6

A forty-four year old woman volunteered to use 0.5 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in four to five minutes. c) That thechange in sensation lasted more than one hour. d) That she experiencedenhanced wetness, warmth, tingling, sensation, orgasm and quicker toorgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be more than usual. g) That her ability to achieve orgasm waseasier to achieve. h) That the product enhanced her sexual experienceand would like to continue using it. i) That she would purchase theproduct and use it on special occasions and when she needed a boost. j)That she did not experience any unpleasant or unwanted effects.

Case Example 7

A twenty-three year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in a few minutes. c) That the change insensation lasted approximately thirty minutes. d) That she experiencedenhanced warmth, tingling, arousal, sensation, orgasm and quicker toorgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That she did not notice achange in her vaginal lubrication, but her partner did. g) That herability to achieve orgasm was easier to achieve. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it when she needed a boost.j) That she did not experience any unpleasant or unwanted effects exceptfor slight irritation.

Case Example 8

A fifty-four year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in two minutes. c) That the change insensation lasted approximately forty-five minutes. d) That sheexperienced enhanced wetness, warmth, tingling, sensation, and arousal.e) That after using the product, intercourse was more pleasurable andsatisfying than normal. f) That her vaginal lubrication seemed to bemore than normal. g) That her ability to achieve orgasm was easier toachieve. h) That the product enhanced her sexual experience and wouldlike to continue using it. i) That she would purchase the product anduse it routinely. j) That she experienced some slight burning andsoreness. She added that her partner said it made him more sensitive andhe had a better climax.

Case Example 9

A fifty year old woman volunteered to use 0.5 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about five minutes. c) That she didnot pay attention to how long the change in sensation lasted. d) Thatshe experienced enhanced wetness, warmth, tingling, sensation andenhanced orgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That she did not notice achange in her her vaginal lubrication, but her partner noticed increasedlubrication. g) That her ability to achieve orgasm was unchanged. h)That the product enhanced her sexual experience and would like tocontinue using it. i) That she would purchase the product and use itwhen she needed a boost. j) That she did not experience any unpleasantor unwanted effects. She also commented that she could not use itregularly because her partner enjoys oral sex.

Case Example 10

A forty-three year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about ten minutes. c) That the changein sensation lasted approximately one hour. d) That she experiencedenhanced wetness, warmth, tingling, sensation, arousal, orgasm andquicker to orgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be more than usual. g) That her orgasm was easier to achieve.h) That the product enhanced her sexual experience and would like tocontinue using it. i) That she would purchase the product and use it onspecial occasions. j) That she did not experience any unpleasant orunwanted effects other than some minor burning and soreness.

Case Example 11

A thirty-eight year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about ten minutes. c) That the changein sensation lasted approximately two hours. d) That she experiencedenhanced warmth, tingling and arousal. e) That after using the product,intercourse was more pleasurable and satisfying than normal. f) That hervaginal lubrication seemed to be the same as always. g) That her abilityto achieve orgasm was unchanged. h) That the product enhanced her sexualexperience and would like to continue using it. i) That she wouldpurchase the product and use it on special occasions. j) That sheexperienced some minor burning, but did not feel any productimprovements were necessary.

Case Example 12

A twenty-four year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about two minutes. c) That the changein sensation lasted approximately forty-five minutes. d) That sheexperienced enhanced warmth and tingling. e) That after using theproduct, intercourse was more pleasurable and satisfying than normal. f)That her vaginal lubrication seemed to be the same as always. g) Thather ability to achieve orgasm was unchanged. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it on special occasions andwhen she needed a boost. j) That she did not experience any unpleasantor unwanted effects other than some minor burning.

Case Example 13

A forty-seven year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about three minutes. c) That thechange in sensation lasted approximately thirty minutes. d) That sheexperienced enhanced warmth, tingling and sensation. e) That after usingthe product, intercourse was more pleasurable and satisfying thannormal. f) That her vaginal lubrication seemed to be the same as always.g) That her ability to achieve orgasm was unchanged. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it routinely. j) That shedid not experience any unpleasant or unwanted effects.

Case Example 14

A thirty year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about four to five minutes. c) Thatthe change in sensation lasted approximately one and one-half hours. d)That she experienced enhanced wetness, warmth, tingling, fullness(engorgement), sensation, arousal, orgasm, quicker to arousal andquicker to orgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be more than usual. g) That her ability to achieve orgasm wasunchanged. h) That the product enhanced her sexual experience and wouldlike to continue using it. i) That she would purchase the product anduse it on special occasions. j) That she did not experience anyunpleasant or unwanted effects.

Case Example 15

A twenty-five year old woman volunteered to use 0.5 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about five minutes. c) That thechange in sensation lasted approximately one hour. d) That sheexperienced enhanced warmth, tingling, sensation, arousal, orgasm andquicker to orgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be the same as always. g) That it was easier for her toachieve orgasm. h) That the product enhanced her sexual experience andwould like to continue using it. i) That she would purchase the productand use it on special occasions and when she needed a boost. j) That shedid not experience any unpleasant or unwanted effects.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

The entire disclosure of all applications, patents and publications,cited above, and of corresponding U.S. Provisional Application Ser. No.60/214,472, filed Jun. 27, 2000, is hereby incorporated by reference.

What is claimed is:
 1. A topical composition, comprising: effectiveamounts for enhancing or improving female sexual pleasure of (a) borageseed oil, (b) Angelica root; (c) evening primrose oil, and (d) Coleusforskohli extract comprising an effective amount of forskolin.
 2. Thetopical composition of claim 1, further comprising; e) an effectiveamount of vinpocetine.
 3. A method of treating female sexual arousaldisorder, female orgasmic disorder, or female sexual pain disordercomprising administering an effective amount of the composition of claim2.
 4. The topical composition of claim 1, wherein said borage seed oilis 10-99% w/w of said composition, said Angelica pubescens root is0.001-99% w/w of said composition, and said Coleus forskohlii extract is0.001-8% w/w of said composition.
 5. A method of facilitating femalesexual arousal or female sexual response, or heightened female genitalsensation, comprising administering an effective amount of thecomposition of claim
 4. 6. The topical composition of claim 1, furthercomprising a pharmaceutically acceptable topical excipient.
 7. Thetopical composition of claim 6, wherein said excipient is one or moreof: magnesium or salts thereof, ferulic acid, capric/caprylictriglyceride, silica, vitamin E, vitamin E acetate, ascorbyl palmitate,saccharin, fragrances, and flavors.
 8. The topical composition of claim6, further comprising 2-10 wt % deionized distilled water, 0.5-5 wt %sorbitan monooleate, 0.5-5 wt % lecithin and 0.25-2 wt % of flavor an/orfragrance enhancers wherein said weight percentages are based on thetotal weight of the composition.
 9. A method of facilitating femalesexual arousal, female sexual response or heightened female genitalsensation, comprising administering an effective amount of thecomposition of claim
 1. 10. The method of claim 9 wherein said extractof Coleus forskohlii comprises about 80% forskolin.
 11. A method oftreating female sexual arousal disorder, female orgasmic disorder, orfemale sexual pain disorder comprising administering an effective amountof the composition of claim
 1. 12. A method of treating female sexualdystunction, comprising administering an effective amount of thecomposition of claim
 1. 13. A method of facilitating female sexualarousal or female sexual response, or heightened female genitalsensation, comprising administering an effective amount of thecomposition of claim
 2. 14. The topical composition of claim 1 whereinsaid Angelica is Angelica pubescens.
 15. The composition of claim 1wherein said extract of Coleus forskohlii comprises about 80% forskolin.16. The method of claim 11 wherein said extract of Coleus forskohliicomprises about 80% forskolin.
 17. The composition of claim 1, whereinsaid primrose oil comprises 10-99% w/w of said composition.
 18. Thetopical composition of claim 1 wherein said Angelica is Angelicaarchangelica, Angelica sinensis, Angelica sylvestris, Angelicaofficinalis, Angelica acutiloba, Angelica pubescens, Angelica archangel,European Angelica or garden Angelica.